Impact of the aging niche on cancer phenotypes probed using mouse cancer models produced by somatic engineering.

使用体细胞工程产生的小鼠癌症模型探讨衰老生态位对癌症表型的影响。

• 批准号: 10355559
• 负责人: SCOTT W. LOWE
• 金额: $ 53.71万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10355559
• 关键词: Address; Age; Aging; Alleles; Animals; Biological; Biology; Cancer Biology; Cancer Intervention; Cancer Model; Cancer Patient; Cell physiology; Cells; Cellular Metabolic Process; Chronology; DNA Damage; Development; Disease; Engineering; Environment; Environmental Risk Factor; Epigenetic Process; Frequencies; Genetic; Genetically Engineered Mouse; Genomics; Genotype; High Fat Diet; Histologic; Immune; Incidence; Individual; Label; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Methods; Modeling; Molecular; Mus; Mutation; Oncogenic; Organ; Phenotype; Physiological; Physiological Processes; Physiology; Play; Process; Production; Reactive Oxygen Species; Resolution; Risk Factors; Role; Series; Study models; Technology; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Transplantation; Tumor-infiltrating immune cells; age effect; age related; aged; cancer therapy; cell type; cohort; cost; dietary; experience; experimental study; human disease; improved; in vivo; innovation; insight; interest; juvenile animal; malignant stomach neoplasm; molecular phenotype; neoplastic cell; novel; offspring; portability; response; senescence; single cell analysis; success; tool; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

SUMMARY Aging is the greatest risk factor for cancer development, yet the physiological and molecular mechanisms underlying this relationship remain poorly understood. Undoubtedly, one contributing factor is time – i.e. the years or decades needed for a single cell to acquire sufficient mutations to trigger overt disease. However, other factors certainly play a role, including age-related changes in cell metabolism, DNA damage responses, immune cell function, and the abundance of senescent cells. While understanding how these factors influence tumorigenesis will reveal strategies to improve cancer intervention and treatment, facile models to study cancer in aged animals are lacking. Addressing this critical challenge, we incorporate somatic tissue engineering methods to introduce oncogenic mutations directly into the organs of aged mice, thereby obviating the time and costs of intercrossing and aging cohorts of multi-allelic genetically engineered mouse models (GEMMs). We have developed a range of such “non-germline GEMMs” (nGEMMs) of different target organs and cancer genotypes and shown that the resulting cancers recapitulate molecular and histological features of the corresponding human disease. We have also produced nGEMMs using aged mice and shown that the developing tumors have distinct immune infiltrates with different tumor surveillance capabilities. This proposal combines the unique capabilities of nGEMMs with state-of-the-art tissue analyses to assess the contribution of the aged environment to cancer manifestation in different organ contexts and compares results to settings in which dietary or genetic factors uncouple biological age from chronological age. Implementation of advanced single cell methods will produce a detailed picture of cell type and cell state differences in tumors developing in aged animals and perturbation studies will explore tumor cell intrinsic and extrinsic factors underlying age- related phenotypes. The proposed experiments will benefit from combining our expertise in cancer biology with that of Dr. Laura Niedernhofer, who has extensive experience in studying organismal aging. Our studies will establish broadly portable models for studying cancer in aged mice at a breadth and pace that was previously impossible and produce novel insights into how the epigenetic and physiological processes linked to age contribute to an increase in cancer incidence and/or progression.

总结 衰老是癌症发展的最大风险因素，但生理和分子机制 这种关系的根本原因仍然知之甚少。毫无疑问，一个影响因素是时间-即 一个细胞需要几年或几十年才能获得足够的突变来引发明显的疾病。然而，在这方面， 其他因素当然也发挥了作用，包括与年龄相关的细胞代谢变化、DNA损伤反应， 免疫细胞功能和大量衰老细胞。在了解这些因素如何影响 肿瘤发生将揭示改善癌症干预和治疗的策略， 老年动物缺乏。为了应对这一关键挑战，我们将体细胞组织工程 将致癌突变直接引入老年小鼠器官的方法，从而避免了时间和 多等位基因遗传工程小鼠模型（GEMM）的交叉和老化队列的成本。我们 已经开发了一系列针对不同靶器官和癌症的“非生殖系GEMM”（nGEMM 基因型，并表明，由此产生的癌症概括的分子和组织学特征的基因型， 相应的人类疾病。我们还使用老年小鼠生产了nGEMM，并表明， 发展中的肿瘤具有不同的免疫浸润，具有不同的肿瘤监视能力。这项建议 将nGEMM的独特功能与最先进的组织分析相结合， 在不同的器官环境中，老年环境对癌症表现的影响，并将结果与 哪些饮食或遗传因素将生物年龄与实足年龄分开。采用先进 单细胞方法将产生一个详细的图片细胞类型和细胞状态的差异，在肿瘤的发展， 老年动物和扰动研究将探索肿瘤细胞内在和外在因素的年龄， 相关表型这些拟议中的实验将受益于我们在癌症生物学方面的专业知识， Laura Niedernhofer博士在研究生物衰老方面有着丰富的经验。我们的研究将 建立广泛的便携式模型，以研究老年小鼠的癌症，其广度和速度是以前 不可能，并对表观遗传和生理过程如何与年龄相关产生新的见解 导致癌症发病率和/或进展的增加。